Epigenetics of Hypogonadotropic Hypogonadism: Molecular Mimicry between Severe Acute Respiratory Syndrome Coronavirus 2 and KISSR

This study analyzed KISS1 and its receptor KISSR for peptide sharing with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was found that SARS-CoV-2 shares numerous minimal immune pentapeptide determinants with KISSR only. The peptide sharing has a high immunologic potential since almost all the common peptides are present in 101 SARS-CoV-2-derived immunoreactive epitopes. Data are in favor of configuring molecular mimicry as an epigenetic factor that can alter KISSR thus causing the hypogonadotropic hypogonadism syndrome with which altered KISSR associates.


Introduction
The human kisspeptin protein (here referred to as KISS1) and the human kisspeptin receptor protein (here referred to as KISSR) form the hypothalamic system that regulates the gonadotropic axis at puberty and in adulthood. 1 As reviewed by Szydełko-Gorzkowicz et al, 2 KISS1 and KISSR participate in different biological processes in that KISS1 plays an essential role in governing pubertal onset and human reproduction, while alterations of KISSR are responsible for the development of hypogonadotropic hypogonadism syndrome that includes dysfunction of fertility, absent or incomplete sexual maturation, and puberty disorders. 3,4 Recently, clinical reports 5-8 described the ex novo insurgence of hypogonadotropic hypogonadism disorders such as precocious accelerated puberty, hypothalamic amenorrhea, and male hypogonadism, during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In spite of the importance of these clinical data, the issue has been overlooked 9 and, to the best of this author's knowledge, no molecular mechanism that might link the hypogonadotropic hypogonadism syndrome to the exposure to SARS-CoV-2 has been investigated and/or proposed.
Based on these observations, the present study posed a question: could SARS-CoV-2 infection/vaccination play a causal role via molecular mimicry and cross-reactivity in the diseases canonically ascribed to potential genetic variants of KISS1 and KISSR?
Consequently, molecular mimicry analyses were performed as follows. The amino acid (aa) sequences of KISS1 (Uniprot entry number: Q15726, 138 aa) and KISSR (Uniprot entry number: Q969F8, 398 aa) were retrieved from www. uniprot.org/ 10 and dissected into sequential pentapeptides offset by one residue (i.e., MNSLV, NSLVS, SLVSW, and so forth). The resulting pentapeptides were analyzed for occurrences in the SARS-CoV-2 proteome using the peptide match program (research.bioinformatics.udel.edu/peptidematch/ index.jsp). 11 Human coronavirus 229E, Human respiratory syncytial virus B, and Mumps virus were utilized as controls. Pentapeptides were used as probes since a peptide formed by 5 aa residues defines a minimal immune determinant that can induce specific antibodies and specific antigen-antibody interaction. [12][13][14][15] The immunological potential of the peptide matching was analyzed by searching the Immune Epitope DataBase (IEDB, www.iedb.org/) 16 for SARS-CoV-2 immunoreactive epitopes hosting the shared pentapeptides.

Abstract
This study analyzed KISS1 and its receptor KISSR for peptide sharing with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was found that SARS-CoV-2 shares numerous minimal immune pentapeptide determinants with KISSR only. The peptide sharing has a high immunologic potential since almost all the common peptides are present in 101 SARS-CoV-2-derived immunoreactive epitopes. Data are in favor of configuring molecular mimicry as an epigenetic factor that can alter KISSR thus causing the hypogonadotropic hypogonadism syndrome with which altered KISSR associates.
The results of the molecular mimicry analyses are reported in ►Table 1. As a first notable point, ►Table 1 shows that KISSR is the focus of an intense and specific peptide sharing with SARS-CoV-2. Numerically, 8 pentapeptides are common to the SARS-CoV-2 proteome and KISSR, while no sharing occurs with KISS1. In this regard, it has to be underscored that such a dimension of peptide sharing between SARS-CoV-2 and KISSR is unexpected and mathematically impossible. Indeed, assuming that all aa occur with the same frequency, the probability that one identical pentapeptide may occur in two proteins is 1 out of 20 5 (or 1 in 3,200,000 or 0.0000003125), that is, it is close to zero.
Then, the peptide commonality between SARS-CoV-2 and KISSR finds a logical scientific explanation in the close phenetic relationship between viruses and the origin of the eukaryotic cell. In fact, according to the endosymbiotic theory, 17 the first eukaryotic cell (our lineage) originated as a consortium consisting of an archaeal ancestor of the eukaryotic cytoplasm, a bacterial ancestor of mitochondria and a viral ancestor of the nucleus. Evolutionary, such a phenetic relationship, resulted in a sparse distribution of viral sequences in the human proteome. Immunologically, this means that targeting a viral protein inevitably leads to targeting human proteins, thus causing autoimmunity, 18 A second noteworthy point of the present study is the high immunological potential of peptide sharing. Indeed, exploration of IEDB revealed that all shared pentapeptides but one (namely, LRLGS) recur in 101 experimentally validated immunoreactive SARS-CoV-2-derived epitopes (►Table 2). That is, the potential immunologic cross-reactivity between SARS-CoV-2 and KISSR is high and powerfully suggests an autoimmune context for the hypogonadotropic hypogonadism disorders linked to KISSR alterations.

Conclusions
Starting from 2000, 19 this author's lab continuously reported that a massive peptide overlap exists between human and pathogen proteins, thus calling attention to the molecular  mimicry and cross-reactivity issues in immunology and vaccinal protocols. [19][20][21][22][23][24][25][26] Here, this study describes the molecular mimicry and the immunologic cross-reactive potential between SARS-CoV-2 and KISSR, alterations of which are responsible for hypogonadotropic hypogonadism syndrome. 3,4 In essence, this study scientifically explains the clinical reports 5-8 on the onset of hypothalamic-pituitary dysfunctions following the SARS-CoV-2 pandemic and warrants further investigations, also in light of the scarce attention paid to the topic in relation to the emerging infectious disease outbreaks. 9 Clinically, the present data (1) lead to the inclusion of the hypogonadotropic hypogonadism syndrome among the SARS-CoV-2-related disorders that collectively form the coronavirus disease 2019 diseasome and (2) permit to catalog as autoimmune a syndrome until now defined idiopathic. 3,27,28 Funding None

Conflict of Interest
None declared.